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Coinfection of Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus-1 (HIV) is a significant public health concern. Treatment is challenging due to prolonged duration of therapy and drug interactions between antiretroviral therapy (ART) and anti-TB drugs. Noniron gallium meso -tetraphenyl porphyrin (GaTP), a heme mimetic, has shown broad antimicrobial activity. Here, we investigated the efficacy of nanoparticle encapsulating GaTP (GaNP) for the treatment of HIV and Mtb coinfection or single infection in in vitro granuloma structures. GaNP significantly reduced viable Mtb within primary human in vitro granuloma structures infected with Mtb H37Rv-lux and significantly reduced levels of HIV in CD4+ T cells infected with the virus axenically. Similarly, GaNP exhibited significant antimicrobial activity against HIV/Mtb-coinfected granuloma structures created in vitro , which contain the primary immune cells seen in human TB granulomas, including CD4+ T cells and macrophages, as assessed by a luciferase assay for Mtb and p24 ELISA for HIV detection. Furthermore, mechanistic studies revealed that GaTP increases the level of reactive oxygen species and inhibits catalase in Mtb. A significant increase in Mtb nitrate reductase activity was also observed when Mtb was incubated with GaTP and sodium nitrate. Overall, increased oxidative stress and nitrite levels induced by GaTP are consistent with the possibility that GaTP inhibits Mtb aerobic respiration, which leads to incomplete O 2 reduction and a shift to respiration using exogenous NO 3 . These cumulative data continue to support the potential for developing the noniron heme analog GaTP and its nanoparticle GaNP as new therapeutic approaches for the treatment of HIV/Mtb coinfection.

Objective: The study aimed to investigate the clinical outcomes of fetuses diagnosed with isolated mega cisterna magna in utero. Methods: A multicenter retrospective cohort study was conducted across 18 university hospitals from 2010 to 2019. Cases diagnosed with isolated mega cisterna magna, defined as a cisterna magna >10 mm with a normal cerebellar vermis and no cystic dilation of the fourth ventricle, were included. Cases with other central nervous system (CNS) anomalies, extra-central nervous system anomalies, chromosomal abnormalities, or congenital infections were excluded. Maternal demographics, prenatal findings, delivery outcomes, and postnatal outcomes were analyzed. Results: The mean gestational age at initial diagnosis was 28.6 ± 3.9 weeks, and the mean anteroposterior diameter of the cisterna magna was 12.5 ± 3.2 mm. Of the 71 cases initially assessed, 48 (67.6%) showed self-regression in utero. Postnatally, 13 cases (18.3%) had persistent isolated mega cisterna magna, whereas 10 cases (14.1%) were diagnosed with other central nervous system anomalies. Among the persistent isolated mega cisterna magna cases, one child exhibited delayed neurodevelopment. There was a higher incidence of isolated mega cisterna magna in male fetuses, which exhibited a significantly larger mean cisterna magna diameter compared with female fetuses ( P  = .045). Conclusion: Male fetuses exhibited a higher incidence of isolated mega cisterna magna compared with female fetuses and had larger anteroposterior diameters of the cisterna magna. The study demonstrated favorable neurodevelopmental outcomes associated with isolated mega cisterna magna, with self-regression observed in two-thirds of the cases. However, consecutive prenatal and postnatal evaluations for additional central nervous system or extra-central nervous system malformations need to be performed, considering the differences between prenatal and postnatal diagnoses., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To elucidate the impact of poor prognostic factors (PPFs) in daily practice on achieving remission and the requirement for biologic or targeted synthetic DMARDs (b/tsDMARDs) in a large Korean cohort of patients with rheumatoid arthritis (RA)., Methods: Using the KORean Observational study Network for Arthritis (KORONA) database, patients with RA were categorized into three groups based on the number of PPFs (0-1, 2, or≥3): the presence of functional limitation, extra-articular disease, seropositivity, and bone erosions. Factors related to achieving remission and to initiating b/tsDMARDs were evaluated using Cox proportional hazard regression analyses after adjusting confounders., Results: Among 5076 patients with RA, group L (PPF≤1), group M (PPFs 2), and group H (PPFs≥3) were 1788 (35.2%), 2027 (39.9%), and 1261 (24.9%), respectively. Group H had higher disease activity and worse patient-reported outcomes than groups L and M. Among moderately-to-highly active patients at baseline, group H was significantly less likely to attain point (hazard ratio [HR]=0.55, 95% confidence interval [CI] 0.38-0.79) and sustained (HR=0.45, 95% CI 0.21-0.99) Boolean-based remission in 5-year. Groups M (HR=1.47, 95% CI 1.10-1.96) and H (HR=1.69, 95% CI 1.22-2.32) had an increased risk of escalation to b/tsDMARDs, compared to group L among b/tsDMARDs-naïve patients at baseline., Conclusion: Achieving remission was particularly challenging for group H, and more patients in groups M and H initiated b/tsDMARDS during the 5-year observation period. Therefore, the presence of PPFs≥3 significantly influences both patients' outcomes and clinician's treatment decisions regardless of disease activity., (Copyright © 2024 Sociýtý Franýaise de Rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Effective management of rheumatoid arthritis (RA) necessitates the accurate measurement of disease activity using a treat-to-target strategy established as a cornerstone approach. Disease activity assessment tools such as the Disease Activity Score in 28 joints (DAS28), Simplified Disease Activity Index, Clinical Disease Activity Index, and Routine Assessment of Patient Index Data 3 have been internationally validated and recognised. In Korea, the government initiated a quality assessment program mandating routine measurement of DAS28 to ensure high-quality RA management. However, whether the DAS28 is the most suitable disease activity measurement tool in the Korean clinical environment is a topic worth considering. In this review, we comprehensively examined disease activity measurement tools and their performance in the Korean context. We also propose a new strategy for measuring RA disease activity, tailored to the different situations encountered by physicians in routine clinical practice. This review may contribute to the improvement of the quality of care for patients with RA in Korea., Competing Interests: CONFLICT OF INTEREST S.K.C. has been an editorial board member of the Journal of Rheumatic Diseases since June 2020, but has no role in the decision to publish this article., (Copyright © 2024 by The Korean College of Rheumatology. All rights reserved.)

Background: We investigated the impacts of tocolytic agents on maternal and neonatal blood glucose levels in women with gestational diabetes mellitus (GDM) who used tocolytics for preterm labor., Methods: This multi-center, retrospective cohort study included women with GDM who were admitted for preterm labor from twelve hospitals in South Korea. We excluded women with multiple pregnancies, anomalies, overt DM diagnosed before pregnancy or 23 weeks of gestation, and women who received multiple tocolytics. The patients were divided according to the types of tocolytics; atosiban, ritodrine, and nifedipine group. We collected baseline maternal characteristics, pregnancy outcomes, maternal glucose levels during hospitalization, and neonatal glucose levels. We compared the frequency of maternal hyperglycemia and neonatal hypoglycemia among three groups. A multivariate logistic regression analysis was performed to evaluate the contributing factors to the occurrence of maternal hyperglycemia and neonatal hypoglycemia., Results: A total of 128 women were included: 44 (34.4%), 51 (39.8%), and 33 (25.8%) women received atosiban, ritodrine, and nifedipine, respectively. Mean fasting blood glucose (FBG) (112.3, 109.6, and 89.5 mg/dL, P < 0.001) and 2-hour postprandial glucose (PPG2) levels (145.4, 148.3, and 116.5 mg/dL, P = 0.004) were significantly higher in atosiban and ritodrine group than those in nifedipine group. Even after adjusting for covariates including antenatal steroid use, gestational age at admission, and pre-pregnancy body mass index, there was an increased risk of high maternal mean FBG (≥ 95 mg/dL) and PPG2 (≥ 120 mg/dL) levels in the atosiban and ritodrine group than in nifedipine group. The atosiban and ritodrine groups are also at increased risk of neonatal hypoglycemia (< 47 mg/dL) compared to the nifedipine group with the odds ratio of 4.58 and 4.67, respectively ( P < 0.05)., Conclusion: There is an increased risk of maternal hyperglycemia and neonatal hypoglycemia in women with GDM using atosiban and ritodrine tocolytics for preterm labor compared to those using nifedipine., Competing Interests: Hyun Soo Park and Hyun-Joo Seol participated in the Tractocile (atosiban) Advisory Board and received consulting fees from Ferring Pharmaceuticals Korea on October 24, 2023. Other authors have no potential conflicts of interest., (© 2024 The Korean Academy of Medical Sciences.)

Pain accompanied by depressive symptoms is a common reason for seeking medical assistance, and many chronic pain patients experience comorbid depression. The brain-derived neurotrophic factor (BDNF) is a well-known neurotrophin expressed throughout the nervous system, playing a crucial role in neuronal growth and neuroplasticity. This study aimed to examine the effects of exercise on BDNF expression in the nervous system and reserpine (RSP)-induced pain-depression dyad. RSP (1 mg/kg) was subcutaneously administered once daily for three days in mice. The exercise was performed using a rota-rod tester for seven consecutive days following RSP administration. Pain responses were evaluated using von Frey filaments, and depression-like behaviors were assessed through forced swimming and open field tests. Immunofluorescence staining was performed to examine the changes in BDNF expression in the dorsal root ganglion (DRG), spinal cord, and hippocampus. Administration of RSP reduced mechanical paw withdrawal threshold, increased immobility time in the forced swimming test, and decreased movement in the open field test. The immunoreactivity of BDNF was increased in the DRG and spinal dorsal regions, and decreased in the hippocampus after RSP administration. Physical exercise significantly reduced the RSP-induced mechanical hypersensitivity and depression-like behaviors. In addition, exercise suppressed not only the increased expression of BDNF in the DRG and spinal dorsal regions but also the decreased expression of BDNF in the hippocampus induced by RSP administration. These findings suggest that repetitive exercise could serve as an effective and non-invasive treatment option for individuals experiencing both pain and depression by modulating BDNF expression.

Metals play vital roles in biological systems, with iron/heme being essential for cellular and metabolic functions necessary for survival and/or virulence in many bacterial pathogens. Given the rise of bacterial resistance to current antibiotics, there is an urgent need for the development of non-toxic and novel antibiotics that do not contribute to resistance to other antibiotics. Gallium, which mimics iron, has emerged as a promising antimicrobial agent, offering a novel approach to combat bacterial infections. Gallium does not have any known functions in biological systems. Gallium exerts its effects primarily by replacing iron in redox enzymes, effectively inhibiting bacterial growth by targeting multiple iron/heme-dependent biological processes and suppressing the development of drug resistance. The aim of this review is to highlight recent findings on the mechanisms of action of gallium and provide further insights into the development of gallium-based compounds. Understanding the mechanisms underlying gallium's biological activities is crucial for designing drugs that enhance their therapeutic therapies while minimizing side effects, offering promising avenues for the treatment of infectious diseases.

Transcription factors specifically bind to their consensus sequence motifs and regulate transcription efficiency. Transcription factors are also able to non-specifically contact the phosphate backbone of DNA through electrostatic interaction. The homeodomain of Meis1 TALE human transcription factor (Meis1-HD) recognizes its target DNA sequences via two DNA contact regions, the L1-α1 region and the α3 helix (specific binding mode). This study demonstrates that the non-specific binding mode of Meis1-HD is the energetically favored process during DNA binding, achieved by the interaction of the L1-α1 region with the phosphate backbone. An NMR dynamics study suggests that non-specific binding might set up an intermediate structure which can then rapidly and easily find the consensus region on a long section of genomic DNA in a facilitated binding process. Structural analysis using NMR and molecular dynamics shows that key structural distortions in the Meis1-HD-DNA complex are induced by various single nucleotide mutations in the consensus sequence, resulting in decreased DNA binding affinity. Collectively, our results elucidate the detailed molecular mechanism of how Meis1-HD recognizes single nucleotide mutations within its consensus sequence: (i) through the conformational features of the α3 helix; and (ii) by the dynamic features (rigid or flexible) of the L1 loop and the α3 helix. These findings enhance our understanding of how single nucleotide mutations in transcription factor consensus sequences lead to dysfunctional transcription and, ultimately, human disease., (© 2024. The Author(s).)

Background: This study analyzed data from the end-stage renal disease patient registry collected by the Korean Society of Nephrology to explore trends in mortality among dialysis patients from 2001 to 2022., Methods: Mortality was analyzed in two ways: firstly, using the annual mortality rate; and secondly, by assessing survivability after a certain period of time since the initiation of dialysis. Additionally, we categorized the causes of death by disease group annually to observe how the proportions changed., Results: Since 2001, annual mortality for dialysis patients generally declined, except for a rise in 2020 and 2021 among hemodialysis patients. Overall mortality rates for all dialysis patients dropped from 74.2/1,000 person-years in 2001 to 42.3/1,000 person-years in 2022, with a more pronounced decrease in peritoneal dialysis. While survival probability over the 5 years following initiation of dialysis has shown a steady increase, short-term mortality from 2018 to 2020 affected by coronavirus disease 2019 (COVID-19) has shown a yearly increase by age group, with a greater effect in those aged 75 years and older. The leading causes of death for all dialysis patients have changed little, in the order of heart disease, infection, and vascular problems., Conclusion: While annual mortality and survival probability after dialysis initiation have generally improved in dialysis patients, there has been a temporary deterioration during the COVID-19 pandemic, most pronounced in the elderly.

Objective: Giant cell arteritis (GCA) is a large-vessel vasculitis that primarily affects elderly individuals. However, data regarding Korean patients with GCA are scarce owing to its extremely low prevalence in East Asia. This study aimed to investigate the clinical characteristics of Korean patients with GCA and their outcomes, focusing on relapse., Methods: The medical records of 27 patients with GCA treated at three tertiary hospitals between 2007 and 2022 were retrospectively reviewed., Results: Seventeen (63.0%) patients were females, and the median age at diagnosis was 75 years. Large vessel involvement (LVI) was detected in 12 (44.4%) patients, and polymyalgia rheumatica (PMR) was present in 14 (51.9%) patients. Twelve (44.4%) patients had fever at onset. The presence of LVI or concurrent PMR at diagnosis was associated with a longer time to normalization of the C-reactive protein level (p=0.039) or erythrocyte sedimentation rate (p=0.034). During follow-up (median 33.8 months), four (14.8%) patients experienced relapse. Kaplan-Meier analyses showed that relapse was associated with visual loss (p=0.008) and the absence of fever (p=0.004) at onset, but not with LVI or concurrent PMR., Conclusion: Concurrent PMR and LVI were observed in approximately half of Korean patients with GCA, and the elapsed time to normalization of inflammatory markers in these patients was longer. The relapse rate in Korean GCA is lower than that in Western countries, and afebrile patients or patients with vision loss at onset have a higher risk of relapse, suggesting that physicians should carefully monitor patients with these characteristics., Competing Interests: CONFLICT OF INTEREST No potential conflict of interest relevant to this article was reported., (Copyright © 2024 by The Korean College of Rheumatology. All rights reserved.)

The abnormal innate immune response is a prominent feature underlying autoimmune diseases. One emerging factor that can trigger dysregulated immune activation is cytosolic mitochondrial double-stranded RNAs (mt-dsRNAs). However, the mechanism by which mt-dsRNAs stimulate immune responses remains poorly understood. Here, we discover SRA stem-loop interacting RNA binding protein (SLIRP) as a key amplifier of mt-dsRNA-triggered antiviral signals. In autoimmune diseases, SLIRP is commonly upregulated, and targeted knockdown of SLIRP dampens the interferon response. We find that the activation of melanoma differentiation-associated gene 5 (MDA5) by exogenous dsRNAs upregulates SLIRP, which then stabilizes mt-dsRNAs and promotes their cytosolic release to activate MDA5 further, augmenting the interferon response. Furthermore, the downregulation of SLIRP partially rescues the abnormal interferon-stimulated gene expression in autoimmune patients' primary cells and makes cells vulnerable to certain viral infections. Our study unveils SLIRP as a pivotal mediator of interferon response through positive feedback amplification of antiviral signaling., Competing Interests: DECLARATION OF INTERESTS Jaeseon Lee, Soojin Jang, and Kyung Jin Lee are employees of ORGANOIDSCIENCES Ltd. Other authors have no conflict of interest to declare.

Background: We aimed to analyze the effects of an antimicrobial stewardship program (ASP) on the proportion of antimicrobial-resistant pathogens in bacteremia, antimicrobial use, and mortality in pediatric patients., Methods: A retrospective single-center study was performed on pediatric inpatients under 19 years old who received systemic antimicrobial treatment from 2001 to 2019. A pediatric infectious disease attending physician started ASP in January 2008. The study period was divided into the pre-intervention (2001-2008) and the post-intervention (2009-2019) periods. The amount of antimicrobial use was defined as days of therapy per 1,000 patient-days, and the differences were compared using delta slope (= changes in slopes) between the two study periods by an interrupted time-series analysis. The proportion of resistant pathogens and the 30-day overall mortality rate were analyzed by the χ²., Results: The proportion of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae bacteremia increased from 17% (39 of 235) in the pre-intervention period to 35% (189 of 533) in the post-intervention period ( P < 0.001). The total amount of antimicrobial use significantly decreased after the introduction of ASP (delta slope value = -16.5; 95% confidence interval [CI], -30.6 to -2.3; P = 0.049). The 30-day overall mortality rate in patients with bacteremia did not increase, being 10% (55 of 564) in the pre-intervention and 10% (94 of 941) in the post-intervention period ( P = 0.881)., Conclusion: The introduction of ASP for pediatric patients reduced the delta slope of the total antimicrobial use without increasing the mortality rate despite an increased incidence of ESBL-producing gram-negative bacteremia., Competing Interests: The authors have no potential conflicts of interest to declare., (© 2024 The Korean Academy of Medical Sciences.)

Citrus tristeza virus (CTV) is a highly destructive viral pathogen posing a significant threat to citrus crops worldwide. Disease management and crop protection strategies necessitate the development of rapid and accurate detection methods. In this study, we employed Oxford Nanopore sequencing to detect CTV in Citrus unshiu samples. Subsequently, we developed a specific and sensitive detection assay combining CRISPR/Cas12a with reverse transcription-recombinase polymerase amplification. The CRISPR-Cas12a assay exhibited exceptional specificity for CTV, surpassing conventional RT-PCR by at least 10-fold in sensitivity. Remarkably, the developed assay detected CTV in field samples, with zero false negatives. This diagnostic approach is user-friendly, cost-effective, and offers tremendous potential for rapid onsite detection of CTV. Therefore, the CRISPR-Cas12a assay plays a significant role in managing and preserving citrus trees that are free from viruses in the industry., Competing Interests: The author(s) declare no conflict of interest.

Background: The comparative risk of cause-specific mortality in patients with Behçet disease (BD) vs. the general population is not known., Objectives: To compare the risk of all-cause and cause-specific mortality in patients with BD vs. the general population., Methods: Using data from the Korea National Health Insurance Service database for the period 2002-20, we conducted a cohort study comparing patients with BD with the general population, matched according to age and sex (1 : 4 ratio). We used Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality. Subgroup analyses by age and sex were done., Results: We included 24 669 patients with BD and 98 676 age- and sex-matched controls [mean (SD) age 40.5 (12.9) years; 34% male]. During a mean follow-up of 11.9 years, the incidence rate (IR) of death per 100 person-years was 0.36 in patients with BD and 0.29 in controls [hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.20-1.38]. The risk of mortality was highest in the first year after BD diagnosis (HR 2.66, 95% CI 2.09-3.40). Patients with BD died more often in this period as a result of malignancy (HR 1.96, 95% CI 1.30-2.98); cardiovascular (HR 2.68, 95% CI 1.45-4.97), gastrointestinal (HR 3.50, 95% CI 1.35-9.07) and respiratory disease (HR 5.00, 95% CI 1.34-18.62); and infection (HR 3.33, 95% CI 1.02-10.92). Mortality as a result of neurological (HR 1.58, 95% CI 1.06-2.35) or genitourinary disease (HR 2.20, 95% CI 1.43-3.37) was also more common in patients with BD during the overall follow-up. Subgroup analyses showed consistent results. The risk of cardiovascular mortality vs. the general population was higher in younger patients (P = 0.006) and the risk of gastrointestinal mortality was increased in women vs. men (P = 0.04)., Conclusions: This population-based cohort study revealed that the first year after diagnosis is the highest risk period for excess mortality in people with BD. The mortality burden in BD derives from a wide spectrum of organ involvement and should serve as a warning to clinicians about the systemic nature of the disease., Competing Interests: Conflicts of interest This work was designed and conducted independently of the sponsor, and the authors attained the full right for the final wording., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Study Design: Retrospective cohort study., Objective: To compare the incidence of adjacent segmental pathology (ASP) following minimally invasive (MI) vs open transforaminal lumbar interbody fusion (TLIF) and to identify factors linked to ASP requiring reoperation., Methods: This retrospective study reviewed the outcomes of patients who underwent MI-TLIF or open TLIF. Radiographic ASP (RASP) was evaluated using X-ray imaging to distinguish between degenerative changes, spondylolisthesis, and instability in the adjacent spinal segment. Clinical ASP (CASP) was assessed with the visual analog scale score for leg and back pain and the Oswestry disability index. Patient data were collected 1, 2, 5, and 10 years postoperatively. The timing and frequency of ASP reoperation were analyzed., Results: Five years postoperatively, the RASP rate was 35.23% and 45.95% in the MI-TLIF and open TLIF groups. The frequency of CASP differed significantly between the MI-TLIF and open TLIF groups at 1 year postoperatively. The rates of RASP, CASP, and ASP necessitating reoperation were not significantly different 10 years postoperatively. Cranial facet violation significantly affected ASP in both groups. In the open TLIF group, preoperative adjacent segment disc degeneration significantly influenced ASP., Conclusion: The RASP rate at 5 years postoperatively and the CASP rate at 1 year postoperatively differed significantly between groups. There was no difference in the rate of ASP requiring reoperation. Cranial facet violation is a crucial driving factor for ASP after both surgical procedures., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

With an increasing aging population, the mean age of patients with end-stage kidney disease (ESKD) is globally increasing. However, the current clinical status of elderly patients undergoing hemodialysis (HD) is rarely reported in Korea. The current study analyzed the clinical features and trends of older patients undergoing HD from the Korean Renal Data System (KORDS) database. The patients were divided into three groups according to age: <65 years (the young group), n = 50,591 (35.9%); 65-74 years (the younger-old group), n = 37,525 (26.6%); and ≥75 years (the older-old group), n = 52,856 (37.5%). The proportion of older-old group undergoing HD significantly increased in incidence and decreased in prevalence from 2013 to 2022. The median levels of hemoglobin, serum creatinine, albumin, calcium, phosphorus, and intact parathyroid hormone significantly decreased in the older-old group. The proportions of arteriovenous fistula creation and left forearm placement showed decreased trends with age. Although the utilization of low surface area dialyzers increased with age, the dialysis adequacy, including urea reduction ratio and Kt/V was within acceptable range in the older-old group on HD. Over the past 20 years, the mortality rate in the older-old group has increased, with cardiovascular diseases decreasing and infectious diseases increasing. The incidence of elderly patients undergoing HD has increased over time, but the high mortality of the older-old group needs to be solved. Therefore, it is imperative to develop holistic strategies based on age and individual needs for patients with ESKD.

Citrus cultivation plays a pivotal role, making a significant contribution to global fruit production and dietary consumption. Accurate identification of viral pathogens is imperative for the effective management of plant viral disease in citrus crops. High-throughput sequencing serves as an alternative approach, enabling comprehensive pathogen identification on a large scale without requiring pre-existing information. In this study, we employed HTS to investigate viral pathogens infecting citrus in three different regions of South Korea: Jejudo (Jeju), Wando-gun (Wando), and Dangjin-si (Dangjin). The results unveiled diverse viruses and viroids that exhibited regional variations. Notably, alongside the identification of well-known citrus viruses such as satsuma dwarf virus, citrus tatter leaf virus, and citrus leaf blotch virus (CLBV), this study also uncovered several viruses and viroids previously unreported in Korean citrus. Phylogenetic analysis revealed that majority of identified viruses exhibited the closest affilations with isolates from China or Japan. However, CLBV and citrus viroid-I-LSS displayed diverse phylogenetic positions, reflecting their regional origins. This study advances our understanding of citrus virome diversity and regional dynamics through HTS, emphasizing its potential in unraveling intricate viral pathogens in agriculture. Consequently, it significantly contributes to disease management strategies, ensuring the resilience of the citrus industry.

Inducing apoptosis in cancer cells is a primary goal in anti-cancer therapy, but curing cancer with a single drug is unattainable due to drug resistance. The complex molecular network in cancer cells causes heterogeneous responses to single-target drugs, thereby inducing an adaptive drug response. Here, we showed that targeted drug perturbations can trigger state conflicts between multi-stable motifs within a molecular regulatory network, resulting in heterogeneous drug responses. However, we revealed that properly regulating an interconnecting molecule between these motifs can synergistically minimize the heterogeneous responses and overcome drug resistance. We extracted the essential cellular response dynamics of the Boolean network driven by the target node perturbation and developed an algorithm to identify a synergistic combinatorial target that can reduce heterogeneous drug responses. We validated the proposed approach using exemplary network models and a gastric cancer model from a previous study by showing that the targets identified with our algorithm can better drive the networks to desired states than those with other control theories. Of note, our approach suggests a new synergistic pair of control targets that can increase cancer drug efficacy to overcome adaptive drug resistance.

Bone metastasis in cancer patients is a major disease advancement for various types of cancer. Previously, [ 68 Ga]Ga-HBED-CC-bisphosphonate ([ 68 Ga]Ga-P15-041) showed excellent bone uptake and efficient detection of bone metastasis in patients. To accommodate different α- or β - -emitting metals for radionuclide therapy, a novel DOTA-HBED-CC-bisphosphonate (P15-073, 1 ) was prepared and the corresponding [ 68 Ga]Ga- 1 and [ 177 Lu]Lu- 1 were successfully synthesized in high yields and purity. Gallium-68 conjugation to HBED-CC at room temperature and lutetium-177 conjugation to DOTA at 95 °C were verified in model compounds through secondary mass confirmation. These bisphosphonates, [ 68 Ga]Ga- 1 and [ 177 Lu]Lu- 1, displayed high binding affinity to hydroxyapatite in vitro . After an iv injection, it showed excellent uptake in the spine of normal mice, and micro-PET/CT imaging of nude mice model of bone metastasis showed high bone uptake in tumor tissue. The results indicated that [ 68 Ga]Ga/[ 177 Lu]Lu- 1 holds promise as a theranostic radioligand agent for managing cancer bone metastases.

Background: Recent advancements in positron emission tomograph (PET) using prostate specific membrane antigen (PSMA)-targeted radiopharmaceuticals have changed the standard of care for prostate cancer patients by providing more accurate information during staging of primary and recurrent disease. [ 68 Ga]Ga-P16-093 is a new PSMA-PET radiopharmaceutical that demonstrated superior imaging performance in recent head-to-head studies with [ 68 Ga]Ga-PSMA-11. To improve the availability of this new PSMA PET imaging agent, [ 18 F]AlF-P16-093 was developed. The 18 F-analog [ 18 F]AlF-P16-093 has been synthesized manually at low activity levels using [ 18 F]AlF 2+ and validated in pre-clinical models. This work reports the optimization of the production of > 15 GBq of [ 18 F]AlF-P16-093 using a custom automated synthesis platform., Results: The sensitivity of the radiochemical yield of [ 18 F]AlF-P16-093 to reaction parameters of time, temperature and reagent amounts was investigated using a custom automated system. The automated system is a low-cost, cassette-based system designed for 1-pot syntheses with flow-controlled solid phase extraction (SPE) workup and is based on the Raspberry Pi Zero 2 microcomputer/Python3 ecosystem. The optimized none-decay-corrected yield was 52 ± 4% (N = 3; 17.5 ± 2.2 GBq) with a molar activity of 109 ± 14 GBq/µmole and a radiochemical purity of 98.6 ± 0.6%. Run time was 30 min. A two-step sequence was used: SPE-purified [ 18 F]F - was reacted with 80 nmoles of freeze-dried AlCl 3 ·6H 2 O at 65 °C for 5 min followed by reaction with 160 nmoles of P16-093 ligand at 40 °C for 4 min in a 1:1 mixture of ethanol:0.5 M pH 4.5 NaOAc buffer. The mixture was purified by SPE (> 97% recovery). The final product formulation (5 mM pH 7 phosphate buffer with saline) exhibited a rate of decline in radiochemical purity of ~ 1.4%/h which was slowed to ~ 0.4%/h when stored at 4 °C., Conclusion: The optimized method using a custom automated system enabled the efficient (> 50% none-decay-corrected yield) production of [ 18 F]AlF-P16-093 with high radiochemical purity (> 95%). The method and automation system are simple and robust, facilitating further clinical studies with [ 18 F]AlF-P16-093., (© 2024. The Author(s).)

Background: Interactions of plants with biotic stress factors including bacteria, fungi, and viruses have been extensively investigated to date. Plasmodiophora brassicae, a protist pathogen, causes clubroot disease in Cruciferae plants. Infection of Chinese cabbage (Brassica rapa) plants with P. brassica results in the formation of root galls, which inhibits the roots from absorbing soil nutrients and water. Sugar, the major source of carbon for all living organisms including pathogens and host plants, plays an important role in plant growth and development., Objective: To explore the roles of BrSWEET2, BrSWEET13, and BrSWEET14 in P. brassicae resistance, Arabidopsis thaliana T-DNA knockout mutants sweet2, sweet13, and sweet14 were employed., Methods: To isolate total RNA from the collected root nodules, the root tissues washed several times with running water and frozen tissues with liquid nitrogen. Total RNA was extracted using the Spectrum™ Plant Total RNA Kit (SIGMA) and cDNA was synthesized in a 20 μl reaction volume using the ReverTra Ace-α- ® kit (TOYOBO). Real-time PCR was performed in a 10 μl reaction volume containing 1 μl of template DNA, 1 μl of forward primer, 1 μl of reverse primer, 5 μl of 2× iQTM SYBR ® Green Supermix (BioRad), and 2 μl of sterile distilled water. The SWEET genes were genotyped using BioFACT™ 2× TaqBasic PCR Master Mix 2., Results: Both sweet2 and sweet14 showed strong resistance to P. brassicae compared with wild-type Arabidopsis and Chinese cabbage plants and sweet13 mutant plants. Pathogenicity assays indicated that the SWEET2 gene plays an important role in clubroot disease resistance in higher plants., (© 2024. The Author(s) under exclusive licence to The Genetics Society of Korea.)

Korean Renal Data System (KORDS) is a nationwide end-stage renal disease (ESRD) registry database operated by the Korean Society of Nephrology (KSN). Diabetes mellitus is currently the leading cause of ESRD in Korea; this article provides an update on the trends and characteristics of diabetic ESRD patients. The KORDS Committee of KSN collects data on dialysis centers and patients through an online registry program. Here, we analyzed the status and trends in characteristics of diabetic chronic kidney disease stage 5D (CKD 5D) patients using data from 2001 to 2021. In 2021, the dialysis adequacy of hemodialysis (HD) was lower in diabetic CKD 5D patients than in nondiabetic CKD 5D patients, while that of peritoneal dialysis (PD) was similar. Diabetic CKD 5D patients had a higher proportion of cardiac and vascular diseases and were more frequently admitted to hospitals than nondiabetic CKD 5D patients, and the leading cause of death was cardiac disease. From 2001 to 2020, diabetic CKD 5D patients had a higher mortality rate than nondiabetic CKD 5D patients, but in 2021 this trend was reversed. Diabetic PD patients had the highest mortality rate over 20 years. The mortality rate of diabetic HD patients was higher than that of nondiabetic HD patients until 2019 but became lower starting in 2020. There was a decreasing trend in mortality rate in diabetic CKD 5D patients, but cardiac and vascular diseases were still prevalent in diabetic CKD 5D patients with frequent admissions to hospitals. More specialized care is needed to improve the clinical outcomes of diabetic CKD 5D patients.